【正文】 結(jié)構(gòu)分析和其他性狀： ? 化學(xué)結(jié)構(gòu)的證據(jù)： ? 元素分析，紅外光譜，核磁共振，質(zhì)譜，紫外光譜 ? 關(guān)鍵中間體的結(jié)構(gòu)證據(jù)， X射線晶型圖，旋光度 ? 物理化學(xué)特性 : ? 多態(tài)性，熔點， DSC ? 溶解度 ? pKa 和 pH 值 Characterisation ? Impurities : ? Requirements concerning related substances according to the general monograph Substances for Pharmaceutical Use (2034) and ? the Guideline Control of impurities of pharmacopoeial substances ( QWP 1529/04) should be met ? Possible impurities considered as potential impurities arising from the synthesis should be discussed , indicating origin ( staring material, reagent, solvent,catalyst, intermediate or degradation product ? Discussion of possible routes of degradation ? Analytical methods ( LOD and LOQ) 性狀 ? 雜質(zhì) : ? 關(guān)于相關(guān)物質(zhì)的要求，根據(jù)總的專論 《 藥品使用的物質(zhì)（ 2034） 》 ? 應(yīng)符合《 藥品物質(zhì)的雜質(zhì)控制指南 》 ( QWP 1529/04) ? 應(yīng)該對可能的雜質(zhì)進(jìn)行討論，對認(rèn)為是在合成中出現(xiàn)的潛在雜質(zhì)，指出雜質(zhì)起源（起始物料，試劑，溶劑，催化劑，中間體或降解產(chǎn)物 ? 討論降解可能的路線 ? 分析方法 ( LOD 和 LOQ) Characterisation ? Impurities : ? Suitability of the methods of the monograph to control the quality of the substance must be discussed and demonstrated ? Additional impurities above the reporting threshold demonstrating that Ph. Eur Method is suitable ? If Ph. Eur, method not suitable alternative test method including validation is required ? Chromatograms for production batches, with peak area results ? Additional related substances , identification and qualification accord. to the Guidance Imp. In new Drug Substances ( ICH/2737/99) 性狀 ? 雜質(zhì) : ? 必須討論和證明藥典規(guī)定的原料藥質(zhì)量控制方法的適應(yīng)性 ? 添加的雜質(zhì)在報告的閾值之上，以此證明歐洲藥典的方法是合適的 ? 如果歐洲藥典的方法不適應(yīng)，則需要替代的檢測方法，并包括其相關(guān)的驗證。 residual solvents, starting material, intermediates, byproducts, degradation products ? Reporting impurities, quantitative results numerical terms ! ? Reporting threshold, identification threshold, qualification threshold ? NMT 2g/day Ident. %, Qualif. % ? MT 2g/day Ident. %, Qualif. % 活性物質(zhì)的規(guī)格 ? ICH/367/96規(guī)格指南的注釋 ： ? 建立可接受的標(biāo)準(zhǔn)的指南 ? 規(guī)格的說明 ? 檢測規(guī)程，藥典檢測方法的選擇 ? ICH/2737/99 雜質(zhì)檢測指南 ? 雜質(zhì)的分類；殘留溶劑，起始物料，中間體，副產(chǎn)物，降解產(chǎn)物 ? 報告雜質(zhì)，以數(shù)據(jù)定量的結(jié)果！ ? 報告閾值，鑒別閾值，驗證閾值 ? NMT 2g/天， 鑒別的 %, 數(shù)量 % ? MT 2g/天，鑒別的 %,數(shù)量 % Control of the Active substance ? Analytical Proecedures ? Details of the analytical procedures ? In case of TLC methods in the monograph , suitability to detect imp. at relevant threshold ( % or % acc. Max. daily dose) ? TLC method only accepted in rare cases , ? Requirements of suitability , detection and quantification limit have to be considered 活性物質(zhì)的控制 ? 分析規(guī)程 ? 分析規(guī)程的詳細(xì)內(nèi)容 ? 如果是在專論中的 TLC方法，在相關(guān)閾值內(nèi)雜質(zhì)檢測的適應(yīng)性( % 或 % 根據(jù)日常最大計量 ) ? 僅在很少的情況下，可接受 TLC方法 ? 應(yīng)考慮適應(yīng)性，檢測限和定量限的要求 Control of the Active substance ? Validation of Analytical Procedures ? Reference to validation of analytical methods (ICH 381/95 and ICH 281/95)。 ? 典型的圖譜 ? 對于附加的方法，根據(jù)歐洲藥典的一般方法，象殘留溶劑，適應(yīng)性就足夠了 Control of the Active substance ? Batch Analysis ? Description of batches and results of batches ? Results below 1 % for related substances should be reported with 2 digits ? Present actual figures whenever possible instead of only ?plies? ? Analytical results from min. 2 batches, maximum batch size ? Results should include : Date of manufacture, batch size and batch number, place of manufacture, results of analytical test, use of batches 活性物質(zhì)的控制 ? 批分析 ? 批次描述和批次結(jié)果 ? 結(jié)果小于 1％的相關(guān)物質(zhì)應(yīng)用 2位數(shù)報告 ? 現(xiàn)在的實際數(shù)據(jù)，每當(dāng)可能時只是代替“遵守 ” ? 分析結(jié)果從最少 2批到最大批數(shù)量 ? 結(jié)果應(yīng)當(dāng)包括 : 制造日期 , 批大小和批號 , 制造地點 , 分析檢測結(jié)果 , 批的使用 Control of the Active substance ? Justification of Specification ? See Note for Guidance on Specification, impurity testing guideline, residual solvents ? 5 Reference Standards or Materials ? Specifications, full analytical and physicochemical charcterisation, impurities etc. ? Reference substances ( primary and secondary) incl. full analytical results or Ph. Eur. CRS ? 6 Container Closure System ? Description of bulk storage container closure ? Specification of primary packaging material ( . Poleythylene bags) ad secondary packaging ( . fibre drums, metal drums) ? 活性物質(zhì)的控制 ? 規(guī)格的解釋 ? 查看指南中有關(guān)規(guī)格，雜質(zhì)檢測指南，殘留溶劑的注解 ? 5 對照品或?qū)φ瘴? ? 規(guī)格，完整的分析和物理化學(xué)特性，雜質(zhì)等 ? 對照品（基準(zhǔn)和二級）包括完整的分析結(jié)果或 EP標(biāo)準(zhǔn)品 ? 6 容器密閉系統(tǒng) ? 存放物料的密閉容器的說明 ? 第一層包裝材料（例如聚乙烯袋）和第二層包裝（例如纖維桶，金屬桶）的規(guī)格 7 Stability ? Post approval stability Protocol and mitment ? Retest period may be attributed based on extrapolation , see NfG on stability testing ? Stability Data ? Detailed results in tabular format, ? Stability testing according to ICH guideline ? information on the analytical procedures ( validation if necessary ) 7 穩(wěn)定性 ? 公布批準(zhǔn)的穩(wěn)定性方案和執(zhí)行 ? 復(fù)測周期可以基于外推法來定性，參見 NfG 穩(wěn)定性試驗 ? 穩(wěn)定性數(shù)據(jù) ? 以表格形式的詳細(xì)結(jié)果 ? 根據(jù) ICH指南進(jìn)行穩(wěn)定性試驗 ? 基于分析規(guī)程（如果必要須驗證）的信息 References ? Notice to applicants (NTA) Volume 2 B CTD Module 3 S ? Guideline on the chemistry of new active substances ? Validation of analytical methods , Analytical procedures methodology ICH ? Stability testing, photostability testing ICH ? Impurities testing guideline , residual solvents ICH. ? Note for Guidance on Specifications 參考文獻(xiàn) ? 通知申請者 (NTA) 第 2冊 B CTD 模塊 3 S ? 新活性物質(zhì)化學(xué)部分指南 ? ICH 分析方法驗證 , 分析規(guī)程方法學(xué) ? ICH 穩(wěn)定性試驗 , 光穩(wěn)定性試驗 ? ICH 雜質(zhì)試驗指南，殘留溶劑 ? 指南中關(guān)于規(guī)格的注意 ALFRED E. TIEFENBACHER (GmbH amp。 Co) VanderSmissenStr. 1 22767 Hamburg Germany Tel.: +49404418090 Fax.: +494044180926 Mail.: Application form – Request for New Certificate of Suitability 申請表－－ 新適應(yīng)性證書的要求 Certification procedure ? Application at the EDQM (European Directorate for the Quality of Medicines) ? How to apply ? ? Application form ? Procedere ? Timetable 證明程序